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// Amos Toren 1 , Tatyana Pismenyuk 1 , Michal Yalon 1 , Shani Freedman 1 , Amos J. Simon 1 , Tamar Fisher 1 , Itai Moshe 1 , Juergen K.V. Reichardt 2 , Shlomi Constantini 3 , Yael Mardor 4 , David Last 4 , David Guez 4 , Dianne Daniels 4 , Moria Assoulin 4 , Ruty Mehrian-Shai 1 1 Pediatric Hemato-Oncology, Edmond and Lilly Safra Children's Hospital and Cancer Research Center, Sheba Medical Center, Tel Hashomer Affiliated to The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel 2 YachayTech University, Urcuqui, Ecuador 3 Department of Pediatric Neurosurgery, Dana Children’s Hospital, Tel-Aviv-Sourasky Medical Center, Israel 4 The Advanced Technology Center, Sheba Medical Center, Tel Hashomer Affiliated to The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel Correspondence to: Ruty Mehrian-Shai, email: Ruty.Shai@sheba.health.gov.il Keywords: glioblastoma multiforme, temozolomide, chemosensitivity, proliferation, zinc Abbreviations: GBM: Glioblastoma multiforme; TMZ: Temozolomide; ZnCl 2 : Zinc chloride Received: May 30, 2016 Accepted: July 19, 2016 Published: August 19, 2016 ABSTRACT Temozolomide (TMZ) is an alkylating agent that has become the mainstay treatment of the most malignant brain cancer, glioblastoma multiforme (GBM). Unfortunately only a limited number of patients positively respond to it. It has been shown that zinc metal reestablishes chemosensitivity but this effect has not been tested with TMZ. Using both in vitro and in vivo experimental approaches, we investigated whether addition of zinc to TMZ enhances its cytotoxicity against GBM. In vitro cell viability analysis showed that the cytotoxic activity of TMZ was substantially increased with addition of zinc and this response was accompanied by an elevation of p21, PUMA, BAX and Caspase-3 expression and a decrease in growth fraction as manifested by low ki67 and lower colony formation. Analysis of GBM as intracranial xenografts in athymic mice and administration of concurrent TMZ and zinc yielded results consistent with those of the in vitro analyses. The co-treatment resulted in significant reduction in tumor volume in TMZ/zinc treated mice relative to treatment with TMZ alone. Our results suggest that zinc may serve as a potentiator of TMZ therapy in GBM patients.

Background Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor. Even with vigorous surgery, radiation and chemotherapy treatment, survival rates of GBM are very poor and predictive markers for prognosis are currently lacking. Methods We performed whole genome expression studies of 67 fresh frozen untreated GBM tumors and validated results by 210 GBM samples’ expression data from The Cancer Genome Atlas. Results and discussion Here we show that in GBM patients, high metallothionein (MT) expression is associated with poor survival whereas low MT levels correspond to good prognosis. Furthermore we show that in U87 GBM cell line, p53 is found to be in an inactive mutant-like conformation concurrently with more than 4 times higher MT3 expression level than normal astrocytes and U251GBM cell line. We then show that U87- p53 inactivity can be rescued by zinc (Zn). Conclusions Taken together, these data suggest that MT expression may be a potential novel prognostic biomarker for GBM, and that U87 cells may be a good model for patients with non active WT p53 resulting from high levels of MTs.